The present invention relates to a method of effecting the modulation of differentiation of cells by serum factors and inhibitors of Protein Kinase C. More particularly, the present invention relates to the use of sphingosine and its analogs to promote cellular differentiation.
Differentiation is the modification of cells in structure or function during their course of development. Recent approaches to therapy for various types of cancer have focused on drugs that induce the maturation of the aberrant, differentiation-resistant cells causing the disease. One example of such a compound is retinoic acid, which is a less toxic analog of vitamin A. Retinoic acid has been found to be a potent inducer of differentiation in established myeloid cell lines, as well as primary cultures of cells isolated from patients with promyelocytic leukemia.
However, a problem exists in that certain cellular functions can be controlled by biological response modifiers only under artificial conditions. It has been found that leukemic cells are less responsive in patients than when isolated from bone marrow and cultured in nutrient-rich medium supplemented with fetal calf serum. The success of retinoic acid therapy for a leukemia patient is typically predicted by determining the ability of the compound to induce differentiation of cells isolated from bone marrow and cultured in such medium. Clinical trials and case reports indicate that retinoic acid only induces differentiation in some patients and that the effectiveness of retinoic acid therapy is limited because many patients still develop infections to which they ultimately succumb. Furthermore, in many of the patients who do show improvement, the retinoic acid eventually ceases to cause differentiation and the leukemic cells proliferate.
There exists a need, therefore, for an improved method of controlling cellular differentiation and function using biological response modifiers.
There also exists a need for such a method which encourages differentiation under in-vivo conditions.